QuestionHow do placebo treatments affect pain processing in the brain?

FindingsThis systematic meta-analysis of single-participant functional magnetic resonance imaging data of 603 healthy participants from 20 studies found that placebo treatments against experimental pain have moderate effects on pain reports, but very small effects on the neurologic pain signature, a cerebral measure of nociceptive pain.

MeaningPlacebo analgesia seems to be predominantly mediated by networks different from those underlying the primary processing of noxious stimuli.

Data SourcesMedline (PubMed) was searched from inception to May 2015; the search was augmented with results from previous meta-analyses and expert recommendations.

Study SelectionEligible studies were original investigations that were published in English in peer-reviewed journals and that involved functional neuroimaging of the human brain with evoked pain delivered under stimulus intensity-matched placebo and control conditions. The authors of all eligible studies were contacted and asked to provide single-participant data.

Data Extraction and SynthesisData were collected between December 2015 and November 2017 following the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data guidelines. Results were summarized across participants and studies in a random-effects model.

Main Outcomes and MeasuresThe main, a priori outcome was NPS response; pain reports were assessed as a secondary outcome.

ResultsWe obtained data from 20 of 28 identified eligible studies, resulting in a total sample size of 603 healthy individuals. The NPS responses to painful stimulation compared with baseline conditions were positive in 575 participants (95.4%), with a very large effect size (g = 2.30 [95% CI, 1.92 to 2.69]), confirming its sensitivity to nociceptive pain in this sample. Placebo treatments showed significant behavioral outcomes on pain ratings in 17 of 20 studies (85%) and in the combined sample (g = −0.66 [95% CI, −0.80 to −0.53]). However, placebo effects on the NPS response were significant in only 3 of 20 studies (15%) and were very small in the combined sample (g = −0.08 [95% CI, −0.15 to −0.01]). Similarly, analyses restricted to studies with low risk of bias (g = −0.07 [95% CI, −0.15 to 0.00]) indicated very small effects, and analyses of just placebo responders (g = −0.22 [95% CI, −0.34 to −0.11]) indicated small effects, as well.

Conclusions and RelevancePlacebo treatments have moderate analgesic effects on pain reports. The very small effects on NPS, a validated measure that tracks levels of nociceptive pain, indicate that placebo treatments affect pain via brain mechanisms largely independent of effects on bottom-up nociceptive processing.